Concomitant cryoballoon ablation and percutaneous closure of left atrial appendage in patients with atrial fibrillation
Concomitant cryoballoon ablation and percutaneous closure of left atrial appendage in patients with atrial fibrillation
Gaetano Fassini 1
Sergio Conti 1
Massimo Moltrasio 1
Anna Maltagliati 0
Fabrizio Tundo 1
Stefania Riva 1
Antonio Dello Russo 1
Michela Casella 1
Benedetta Majocchi 1
Martina Zucchetti 1
Eleonora Russo 1
Vittoria Marino 1
Mauro Pepi 0
Claudio Tondo 1
0 Imaging Department, Centro Cardiologico Monzino, IRCCS , Via Parea 4, Milan 20138 , Italy
1 Cardiac Arrhythmia Research Centre, Department of Cardiovascular Sciences, University of Milan, Centro Cardiologico Monzino, IRCCS , Via Parea 4, Milan 20138 , Italy
Aims Pulmonary veins (PVs) isolation is the cornerstone of atrial fibrillation (AF) ablation and can be achieved either by conventional radiofrequency ablation or by cryoenergy. Left atrial appendage (LAA) closure has been proposed as alternative treatment to vitamin K antagonists (VKA). We aimed to evaluate the feasibility of combining cryoballoon (CB) ablation and LAA occlusion in patients with AF and a high thromboembolic risk or contraindication to antithrombotic therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods Thirty-five patients (28 males, 74 + 2 years) underwent CB ablation. Left atrial appendage occlusion was carried out by and results using two occluder devices (Amplatz Cardiac Plug, ACP, St. Jude Medical, MN, USA, in 25 patients; Watchman, Boston Scientific, MA, USA, in 10 patients). Thirty patients (86%) had previous stroke/TIA episodes, 6 patients (17%) had major bleeding while on VKA therapy, and 7 patients (20%) had inherited bleeding disorders. Over the follow-up (24 + 12 months), atrial arrhythmias recurred in 10 (28%) patients. Thirty patients (86%) had complete sealing; 5 patients (14%) showed a residual flow (,5 mm) at first transoesophageal echocardiography (TEE) check, while at 1-year TEE residual flow was detected in 3 patients. In 13 patients (37%), VKA therapy was immediately discontinued. Six patients (17%) received novel oral anticoagulants treatment and then discontinued 3 months thereafter. No device-related complications or clinical thromboembolic events occurred. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion Combined CB ablation and LAA closure using different devices appears to be feasible in patients with non-valvular AF associated with high risk of stroke or contraindication to antithrombotic treatment. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Pulmonary vein isolation (PVI) is regarded as the cornerstone to
treat atrial fibrillation (AF) by means of transcatheter ablation.1,2
This target can be achieved by conventional point-to-point
radiofrequency current delivery or by using cryoenergy through a specific
balloon-designed platform. Furthermore, AF is the most challenging
arrhythmia to treat in the general population, due to the
unsatisfactory efficacy provided by antiarrhythmic drug therapy and the high
risk of thromboembolic event.3,4 It is reported that the overall
annual risk of stroke is 5% in patients suffering from AF and up to
15% in very high-risk patients.5 Left atrial appendage (LAA) is
undoubtedly the main source of thrombus formation in patients
with non-valvular AF.3 According to the International Guidelines,
anticoagulation treatment needs to be prescribed to patients with
CHA2DS2-VASc score ≥ 1 as to prevent embolic events.6 In the
clinical practice, the administration of vitamin K antagonists (VKA)
or novel oral anticoagulants (NOACs) can carry some critical
disadvantages, such as profuse and frequent bleedings, no compliance,
difficulty to keep a therapeutic range, and frequent interactions
with some dietary components and medications,7 – 9 leading to
† Currently, we are not aware of other studies that have dealt
with the concomitant cryoballoon (CB) ablation and left atrial
appendage (LAA) closure.
† It might be interesting to evaluate the safety and feasibility of
a combined CB ablation and LAA closure using different
† Our study shows that a combined CB ablation and LAA
closure procedure seems to be safe and feasible in patients
with non-valvular AF associated with high risk of stroke or
contraindication to anticoagulation therapy.
Due to the role of LAA in harbouring thrombi, an effective
alternative to anticoagulation treatment is its mechanical occlusion.10,11 The
percutaneous obliteration of LAA, using different device designs, has
been shown to be successful both in a randomized clinical trial12,13
and in prospective and registry studies.14,15 Since patients with
drug-resistant non-valvular AF may have high thromboembolic and/
or bleeding risks as well, we considered the combination of CB AF
ablation and LAA mechanical closure as a valuable treatment strategy.
The rationale of this single-center, observational study was to
evaluate the feasibility and efficacy of the combined approach in patients
who share indication to AF ablation and LAA closure, the latter due
to both high risk of bleeding, previous history of thromboembolic,
or major bleeding events during therapeutic anticoagulation treatment.
In this study, we present the feasibility of this novel combined approach.
Patients with documented, drug-resistant, non-valvular paroxysmal or
early persistent AF (≤12 months) who suffered thromboembolic
events despite appropriate anticoagulation therapy or with a previous
history of major bleedings on therapeutic anticoagulation were
considered suitable for this treatment. For each patient, the CHA2DS2-VASc
and the HAS-BLED scores were calculated. To rule out the presence
of left atrial (LA) and LAA thrombi, all patients underwent
twodimensional (2D) transoesophageal echocardiography (TEE) the day
before the procedure, along with a transthoracic echocardiogram for
the assessment of LA dimension, left ventricular ejection fraction
(LVEF), and valvular function. In the majority of patients, a
preprocedural computed tomography scan or magnetic resonance imaging
was performed in order to assess LA anatomy and LAA dimension and
morphology. Class Ic antiarrhythmic drugs were discontinued prior to
ablation. Exclusion criteria were the occurrence of LA thrombus,
LVEF ≤30%, contraindication to general anaesthesia and very enlarged
LA dimension (≥55 mm or volume ≥30 mL). Since the concomitant
AF catheter ablation and mechanical closure of LAA are not included
in the International Guidelines,8 each patient was fully informed of the
procedure and given a written consent form. The study protocol was
approved by the local ethics committee.
All procedures were carried out under general anaesthesia. Briefly,
through a single transseptal puncture, a 28 mm cryoballoon (CB, Arctic
Front, Medtronic, MN, USA, for the first 10 patients; Arctic Front
Advance, Medtronic, MN, USA, for the remaining 25 patients) was inserted
through a steerable dedicated sheath (FlexCath, Medtronic, MN, USA)
in the LA. Once inflated and wedged in the pulmonary vein (PV) ostium,
contrast dye was injected and PV occlusion was judged visually by the
operator as to achieve a perfect occlusion as much as possible.
According to the manufacturer’s recommendations, a 300 s freeze was
delivered using the first-generation CB, reduced to 240 s in patients
treated with the second-generation CB. Based on the time to PVI,
temperature nadir reached and grade of PVs occlusion a bonus freeze was
provided. The procedure was carried out under oesophageal
temperature monitoring (Esotherm Plus, Fiab). Pulmonary vein activity recording
during cryoenergy delivering was also attempted by positioning the
Achieve catheter as close as possible to the distal portion of the CB
as to determine time to PVI or the occurrence of electrical vein
dissociation. Pulmonary vein isolation was then confirmed by repositioning the
Achieve catheter to the most proximal site of the ostium; in all cases,
bidirectional block along the PV – LA junction was assessed by the
conventional pacing manoeuvres. For cryoenergy applications at the septal
veins, pacing of the ipsilateral phrenic nerve with a 1000 ms cycle length
at the maximum output (12 V @ 2.9 ms) was provided as to avoid
phrenic nerve palsy. During the entire procedure, activated clotting
time was maintained between 300 and 350 s. In the case of acute PV
reconnection, adenosine was infused to investigate the durability of PVI
after 20 – 30 min following ablation in that PV.
Left atrial appendage closure
The Amplatz Cardiac Plug (ACP) device (St. Jude Medical, MN, USA) first
(n ¼ 2) and second releases (n ¼ 23) or the Watchman device
(Watchman, Boston Scientific, MA, USA) was implanted (ACP device in 71% of
patients, n ¼ 25, and Watchman device in 29% of patients, n ¼ 10) right
after the ablation procedure was completed, while the patients were
under general anaesthesia. According to the recently published EHRA/
EAPCI expert consensus statement on catheter-based LAA occlusion,
we avoided to implant a Watchman device if the LAA length was less
than the device diameter, or if the LAA diameter was ,17 or
.30 mm. Differently, an ACP device was chosen if the landing zone
diameter was ,29 mm (31 for Amulet), or if the LAA length was .10 mm
(7.5 for Amulet). Thus, if the LAA anatomy and measurements, previously
evaluated with a baseline TEE, allowed the use of both devices, the choice
was taken according to the best therapeutic strategy for each patient. The
implant was performed under monoplane fluoroscopy and 2D- and
3D-TEE guidance. The FlexCath steerable sheath previously used for
CB ablation was replaced by a 14F long sheath for the ACP device and
14F sheath for the Watchman device and manoeuvred towards the
ostium of the LAA. Throughout these sheaths, LAA angiograms for
determining size and shape were performed. For the positioning of each device,
a size 10–25% larger than the largest diameter of the LAA body (based on
the measurements by both angiography and TEE) was preferred as to
promote an effective compression for device stability. For both devices,
before the releasing process, specific criteria had to be fulfilled, including
no or minimal (,3 mm) residual lateral flow, absence of mitral valve leaflet
interference (ACP cases), correct device position in relation to the
circumflex artery plane, and confirmed device stability at the tug test. Once
released, the position of the device was confirmed by TEE and angiography.
Post-procedural management and follow-up
Patients were discharged 48 h following the procedure, once a TTE and
a fluoroscopy check confirmed the stable position of the LAA occluder
device and the lack of any sign of pericardial effusion.
All patients underwent anticoagulation therapy (VKA or NOACs) for
at least 2 months after PVI.8 In addition, we adopted the
recommendation on the base of device implanted (Figures 1 and 2).
Briefly, after Watchman implantation, aspirin and warfarin for 6 weeks,
followed by aspirin and clopidogrel for 6 months and aspirin lifelong.
PVI + LAA closure
2 months anticoagulation
(VKA, NOAC, LMWH)
or in the case of absolute
aspirin and clopidogrel
for 1 month
aspirin for at least 3 months
Conversely, after ACP implantation, clopidogrel for at least 1 month
in the case of absolute contraindication to anticoagulation therapy
and aspirin for at least 3 months were prescribed. Each patient, except
those with inherited bleeding disorders (n ¼ 7, 20%), was assigned to
VKA or NOAC therapy 24 h after the procedure, preceded by
low-molecular-weight heparin (LMWH) bridging therapy started on
the same day of the procedure. Therefore, the LMWH therapy was
discontinued as soon as the target international normalized ratio (INR) of
2.0 – 3.0 was reached in those patients in whom VKA was chosen. Novel
oral anticoagulants were considered in the case of labile INR or based
on physician’s preference. Patients were followed up in the outpatient
clinic 3 months after the procedure and every 3 months thereafter.
At each visit, a standard 12-lead electrocardiogram (ECG) was obtained
in all patients. Clinical events occurring during the follow-up and
documentation of the events were carefully checked. All patients were
followed up with ECG Holter monitoring at 6 and 12 months after CB
ablation. Antiarrhythmic drugs were administered for the first 3 months
and then tapered over based on the clinical course and patient’s
preference. Moreover, between 30 and 60 days, according to device type, each
patient underwent a TEE investigation to evaluate the proper position of
the LAA device, and to rule out any thrombus and residual leakage. If the
sealing criteria were confirmed, anticoagulation or double antiplatelet
therapy was modified based on the guidelines recommendations.
Transoesophageal echocardiography was repeated at 6 months and 1-year
This was an observational, prospective, single-centre study. Patients’
clinical characteristics are reported as descriptive statistics. Continuous
variables with normal distribution are reported as mean + standard
deviation. Categorical variables are expressed as percentage. A P-value of
,0.05 was considered statistically significant. All statistical tests were
performed using SPSS for Windows 17.0 (SPSS, Chicago, IL, USA).
Thirty-five patients (mean age 72 + 4 years) were included in the
study. The clinical characteristics are reported in Table 1.
Twentyeight patients (80%) had paroxysmal AF and seven patients (20%)
early persistent AF (≤12 months duration). The median
CHA2DS2VASc score was 3, and the HAS-BLED score was 3. Seven patients
(20%) had well-established inherited bleeding disorders (three
patients with von Willebrand type 2 disease and the remaining
four patients with type B haemophilia). Thirty patients (86%) had
a previous stroke, 26 patients despite appropriate anticoagulation
therapy. Besides the seven patients with inherited bleeding
disorders, contraindication to continuous VKA therapy was
ascertained in additional six patients. In these patients, intracranial
bleeding (n ¼ 2) or profuse intestinal haemorrhage (n ¼ 4)
prevented to re-establish therapeutic regimen of anticoagulation.
Furthermore, 23% of patients (n ¼ 8, 3 among those with inherited
bleeding disorders and 5 among those major gastrointestinal
bleeding) had both major bleeding and cerebral ischaemic events
(transient ischaemic attack).
Procedural parameters are reported in Table 2. The whole mean
procedural time was 114 + 32 min for CB ablation and 44 +
12 min for LAA occlusion. Therefore, the overall procedural time
was 165 + 34 min. The fluoroscopic time for the CB ablation
procedure was 24 + 11 min and 9 + 3 min for LAA occlusion. The
entire procedure was performed under general anaesthesia.
In 35 patients, a total number of 132 PVs were identified, including a
left common PV in 8 patients. In all cases, the 28 mm CB was used
(first-generation CB n ¼ 10, second-generation CB n ¼ 25).
Complete PVI was achieved in 34 out of the 35 patients (97%). In one
patient, treated with the first-generation CB, the right inferior PV
was not successfully occluded and, therefore, PVI was then achieved
through radiofrequency applications. The average number of
balloon applications per patients to achieve PVI was 8.75. Specific
CB procedure-related complications occurred in two patients
with transient phrenic nerve palsy, while ablating at the right
superior PV. The nadir of temperature at that vein was below 2558C in
both cases. Complete resolution of the phrenic nerve injury was
demonstrated in both patients by Days 24 and 60, respectively.
Pulmonary vein isolation was then checked on between 20 and 30 min
after ablation. Acute reconnection was demonstrated in 5 veins
(4%) (2 left common PVs and 3 at the inferior margin of the
LIPV). In four of these veins, the first-generation CB was used.
Left atrial appendage occlusion
Occluder devices for LAA were implanted under fluoroscopy and
TEE guidance right after the PVI was concluded. Once the size
and shape of the LAA were determined by performing selected
angiograms and TEE measurements, the chosen device (ACP or
At a mean follow-up of 24 + 12 months, atrial arrhythmias (defined
as AF or atrial flutter/atrial tachycardia) occurred in 29% of patients
(n ¼ 10); 50% of them underwent a redo procedure, 3 patients
developed persistent AF and refused to undergo an additional ablation;
the remaining 2 patients were successfully managed with
antiarrhythmic drugs. The redo ablation procedures were guided by
EnSite NavX mapping system: PV – LA reconnection of at least one PV
was detected in all patients (Table 3).
Table 3 Follow-up
Patients (n 5 35)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Months, mean + SD 24 + 12
Arrhythmia recurrence, n (%) 10/35 (29%)
Redo ablation, n (%) 5/35 (14%)
TEE evaluation, n (%)
First TEE, complete sealing 30/35 (86%)
First TEE, minimal leaking (,5 mm) 5/35 (14%)
12 months TEE, complete sealing 32/35 (91%)
Stroke/TIA, n (%) 0/35 (0%)
Device embolization/device thrombus, n (%) 0/35 (0%)
VKA off, n (%) 30/35 (86%)
Death, n (%) 0/35 (0%)
TEE, transoesophageal echocardiography; TIA, transient ischaemic attack; VKA,
vitamin K antagonists.
Left atrial appendage closure
In each patient, TEE evaluation was established between at 1, 6,
and 12 months. Thirty patients (86%) had complete sealing, while
the remaining 5 patients (14%) showed a persistent minimal residual
flow (between 2 and 4 mm) at 180 days; the further check at 1 year
revealed persistent residual flow in 3 patients. In no instances, device
embolization or thrombus formation on surface device was
detected. More importantly, no thromboembolic events had
occurred. In particular, the expected a priori stroke rate was ≈4%/
year, whereas the observed 2-year rate was 0%. However, the
risk reduction was not statistically significant, because in a sample
of 35 subjects, an observed 2-year rate of 0% is compatible with a
baseline risk ranging from 0 to ≈5%/year.
Post-procedural anticoagulation management
In 13 patients with major contraindication to anticoagulation
therapy (37%; those who were known having inherited bleeding
disorders and previous cerebral and profuse gastrointestinal
haemorrhage), subcutaneous LMWH was administered for 2 months,
followed by single antiplatelet therapy. Among the remaining
patients, anticoagulation strategy followed the main
recommendations with the exception of 6 patients (17%) who received NOAC
treatment for the first 3 months (dabigatran in 4 patients and
rivaroxaban in 2 patients, respectively).
We reported a study of combined CB ablation of AF and LAA
closure in a population of patients with non-valvular AF and a high risk of
stroke or strong contraindication to anticoagulant treatment. The
findings of the study confirm the feasibility of such an approach
and indicate that it can be proposed as an effective alternative
treatment to a very selected category of patients.
Swaans et al.15 first published clinical results on LAA occlusion in
combination with AF ablation in a single procedure. Recently, Calvo
et al.16 reported the feasibility of this combined approach using
radiofrequency energy delivery and Watchman or ACP devices.
Even if our experience confirms the feasibility of the approach, there
are differences between our experience and these studies. First, in
our study, CB ablation was elected as privileged energy source to
achieve PVI. Based on experimental data, we hypothesized that the
potential injury (i.e. endothelial disruption, thrombus formation)17
of the tissue at the ridge between the left superior PV and the
LAA, and around the LAA itself, could be lower using cryoenergy
compared with conventional radiofrequency energy. According to
the latest AF ablation guidelines, CB ablation is regarded as an
alternative to radiofrequency when aiming at PVI. Finally, as well as in the
study of Calvo et al., two different types of LAA occluder were used in
our study, confirming the effectiveness of the procedure regardless of
the design of the device. Differently, the whole safety profile of our
approach was uneventful regarding major complications.
Successful PVI with CB was achieved in all patients but one,
confirming the high success rate of the approach. It is critical to
highlight the fact that in this patient, failure of PVI was limited only to the
right inferior PV when using the first-generation CB. Interestingly,
the revised design of the second-generation CB as well as the
dedicated sheath allowed a further increase of the acute success of PVI.18
Five out of 10 patients who had arrhythmia recurrences underwent
a redo procedure: careful electroanatomical mapping by EnSite Navx
provided demonstration of LA– PV reconnection of at least 1 PV in all
patients (mean number per patient: 1.3 + 0.4). Interestingly, 4 out of
5 patients were treated with the first-generation CB during the index
procedure. At a mean follow-up of 24 + 12 months, the success rate
of a single procedure was 71%; while including the redo ablation, the
overall success rate reached 84%.
In this study, successful implantation of LAA occluder device was
achieved in all patients, regardless of the device used. This confirms
the high success rate of the procedure already reported in previous
study.19 Complete sealing was accomplished in a high percentage of
patients (86%, increased to 92% at 1-year TEE check); only in 3
patients a residual flow (,5 mm) persisted over time. Even the
persistence of minimal, residual flow is not considered predictor
of potential thromboembolic events,20 and longer TEE follow-up
may be considered in patients who present this finding.
In our population, no thromboembolic events were reported
over the entire follow-up, suggesting that LAA occlusion and
reduced probability to have arrhythmia recurrences after ablation,
may constitute a valid option of treatment considering the
particularly high risk of embolic events as well as the high predisposition to
bleeding. It could be argued that combining ablation with LAA
mechanical occlusion may bear some disadvantages, such as the
need to keep the patient on anticoagulation for at least 2 – 3 months
after the procedure. Although an interesting simplified
anticoagulation protocol has been proposed after PVI by Duytschaever et al.,21
unfortunately we cannot adopt this strategy due to the high
thromboembolic risk of the population enrolled in our study.
However, in our preliminary experience, no haemorrhagic events were
observed, even in those patients presenting with haemorrhagic
tendency due to inherited bleeding diseases. Moreover, in this
subpopulation, in which antithrombotic treatment for AF can be a
challenge, even the NOAC drugs, at least non-inferior to VKA
with a lower rate of intracranial bleeding as the most significant
benefit, may bear the same bleeding risk. Also, we need to highlight
the concept that patients with prior severe bleeding complications
during VKA therapy or at high risk of bleeding do not represent
an attractive population to be treated with NOACs. Since the
longterm success rate of catheter ablation seems to be around 50 – 60%
following single procedure,22 thus implying the need for
anticoagulation therapy continuation, the combined procedure may
result particularly helpful in some specific setting of patients deemed
to undergo AF ablation: (a) patients with non-valvular AF and prior
ischaemic event and (b) patients with clear contraindication to VKA
therapy. Finally, considering the incidence of major complications
related to AF ablation and LAA percutaneous closure which share the
same procedural steps (vascular access, anticoagulation, transseptal
puncture), the combination of PVI with LAA closure in a single step
reduces the risks associated to a repeated LA procedure.19,23
We acknowledge some limitations of our study. The number of
patients is quite limited and prevented any final conclusion on safety
due to the fact that the study is a non-randomized report. The
main scope of the study was the feasibility of the approach, and
we did not compare this strategy with AF ablation and LAA
occlusion performed in two separate steps. At the end of the follow-up
period, antithrombotic was not discontinued in all patients. This was
due to the fact that in some patients, the referred cardiologists were
the primary treating physicians and felt to keep patients on
antithrombotic treatment, despite good TEE results. Holter recording
was used in fixed time frame over the follow-up, and this might
have limited the chance to detect asymptomatic AF episodes,
favouring overestimation of the success rate of ablation.
Furthermore, we neither did carry out cost-effectiveness evaluation of
the combined strategy.
Combined CB ablation of PV and LAA mechanical closure appears
to be feasible in patients with non-valvular AF associated with high
risk of stroke or specific contraindication to antithrombotic
treatment (VKA/NOACs). For the time being, this approach needs to
be limited to specific and well-selected patients while randomized
clinical trials are warranted as to define the benefit and
costeffectiveness of this interventional strategy.
C.T. received throughout the 2015 consulting fees/honoraria not
directly related to the LAA closure procedure using the Amplatzer device.
Conflict of interest: G.F. and M.M. received consulting
fees/honoraria from Medtronic, Inc. C.T. received consulting fees/honoraria
from St. Jude Medical; Medtronic, Inc.; and Boston Scientific Corp.
1. Wazni OM , Marrouche NF , Martin DO , Verma A , Bhargava M , Saliba W et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial . JAMA 2005 ; 293 : 2634 - 40 .
2. Mohanty S , Mohanty P , Di Biase L , Bai R , Santangeli P , Casella M et al. Results from a single-blind, randomized study comparing the impact of different ablation approaches on long-term procedure outcome in coexistent atrial fibrillation and flutter (APPROVAL) . Circulation 2013 ; 127 : 1853 - 60 .
3. Blackshear JL , Odell JA . Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation . Ann Thorac Surg 1996 ; 61 : 755 - 9 .
4. Goldman ME , Pearce LA , Hart RG , Zabalgoitia M , Asinger RW , Safford R et al. Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke Prevention in Atrial Fibrillation (SPAF-III)) . J Am Soc Echocardiogr 1999 ; 12 : 1080 - 7 .
5. Lloyd-Jones DM , Wang TJ , Leip EP , Larson MG , Levy D , Vasan RS et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study . Circulation 2004 ; 110 : 1042 - 6 .
6. Camm AJ , Lip GY , De Caterina R , Savelieva I , Atar D , Hohnloser SH et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association . Europace 2012 ; 14 : 1385 - 413 .
7. Eikelboom JW , Wallentin L , Connolly SJ , Ezekowitz M , Healey JS , Oldgren J et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial . Circulation 2011 ; 123 : 2363 - 72 .
8. Hylek EM , Evans-Molina C , Shea C , Henault LE , Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation . Circulation 2007 ; 115 : 2689 - 96 .
9. Wallentin L , Yusuf S , Ezekowitz MD , Alings M , Flather M , Franzosi MG et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial . Lancet 2010 ; 376 : 975 - 83 .
10. Meier B , Blaauw Y , Khattab AA , Lewalter T , Sievert H , Tondo C et al. EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion . Europace 2014 ; 16 : 1397 - 416 .
11. Lewalter T , Kanagaratnam P , Schmidt B , Rosenqvist M , Nielsen-Kudsk JE , Ibrahim R et al. Ischaemic stroke prevention in patients with atrial fibrillation and high bleeding risk: opportunities and challenges for percutaneous left atrial appendage occlusion . Europace 2014 ; 16 : 626 - 30 .
12. Fountain RB , Holmes DR , Chandrasekaran K , Packer D , Asirvatham S , Van Tassel TR et al. The PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation) trial . Am Heart J 2006 ; 151 : 956 - 61 .
13. Holmes DR , Reddy VY , Turi ZG , Doshi SK , Sievert H , Buchbinder M et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial . Lancet 2009 ; 374 : 534 - 42 .
14. Meier B , Blauw Y , Khattad AA , Lewalter T , Sievert H , Tondo C et al. EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion . Europace 2014 ; 16 : 1397 - 416 .
15. Swaans MJ , Post MC , Rensing BJ , Boersma LV . Ablation for atrial fibrillation in combination with left atrial appendage closure: first results of a feasibility study . J Am Heart Assoc 2012 ; 1 : e002212 .
16. Calvo N , Salterain N , Arguedas H , Macias A , Esteban A , Garcia de Yebenes M et al. Combined catheter ablation and left atrial appendage closure as a hybrid procedure for the treatment of atrial fibrillation . Europace 2015 ; 17 : 1533 - 40 .
17. Khairy P , Chauvet P , Lehamann J , Lambert J , Macle L , Tanguay JF et al. Lower incidence of thrombus formation with cryoenergy versus radiofrequency catheter ablation . Circulation 2003 ; 107 : 2045 - 50 .
18. Furnkranz A , Bordignon S , Schmidt B , Gunawardene M , Schulte-Hahn B , Urban V et al. Improved procedural efficacy of pulmonary vein isolation using the novel second-generation cryoballoon . J Cardiovasc Electrophysiol 2013 ; 24 : 492 - 7 .
19. Reddy VY , Holmes D , Doshi SK , Neuzil P , Kar S. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry . Circulation 2011 ; 123 : 417 - 24 .
20. Viles-Gonzalez JF , Kar S , Douglas P , Dukkipati S , Feldman T , Horton R et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients with Atrial Fibrillation) substudy . J Am Coll Cardiol 2012 ; 59 : 923 - 9 .
21. Duytschaever M , Berte B , Acena M , De Meyer G , Bun SS , Van Heuverswyn F et al. Catheter ablation of atrial fibrillation in patients at low thrombo-embolic risk: efficacy and safety of a simplified periprocedural anticoagulation strategy . J Cardiovasc Electrophysiol 2013 ; 24 : 855 - 60 .
22. Weerasooriya R , Khairy P , Litalien J , Macle L , Hocini M , Sacher F et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol 2011 ; 57 : 160 - 6 .
23. Cappato R , Calkins H , Chen SA , Davies W , Iesaka Y , Kalman J et al. Updated worldwide surveys on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation . Circ Arrhythm Electrophysiol 2010 ; 3 : 32 - 8 .